The primary objective of this Phase I STTR project is to develop an effective, peptide-based nicotine vaccine for use in humans capable of inducing a robust, nicotine-specific antibody (Ab) response with little or no inflammatory side effects. This will be accomplished by a vaccine design in which a conformationally biased, response-selective agonist Of C5a (YSFKPMPLaR) is used as a molecular adjuvant, a nicotine hapten is used as the target antigen (Ag), and a nonhuman B cell epitope is used to assist hapten processing by antigen presenting cells (APC). The ability of such vaccines to induce anti-nicotine responses will be assessed by vaccinating rats in the absence of added adjuvant and demonstrating: 1) the presence of nicotine-specific Abs in immune sera and 2) an attenuation of nicotine-induced psychoactive effects in two well-established rat models of nicotine dependence - locomotor activity and drug appetitive conditioning. Validation of this peptide-based nicotine vaccine represents the first step toward realization of the broad, commercial objective sought by this project, which is to use vaccination to nicotine with such vaccines as a standard therapeutic regimen for smoking cessation and maintenance of long term compliance. As has been shown in rats, the therapeutic effect in humans will result from the ability of Abs generated in response to the vaccine to bind circulating nicotine with high affinity/selectivity, thereby decreasing nicotine distribution to the brain where it exerts its addictive effects. The central design feature of this nicotine vaccine design is YSFKPMPLaR, which has been shown to be n effective molecular adjuvant in the induction of Ab responses to peptide and non-peptide Ags. Thus, it is hypothesized that an effective YSFKPMPLaR-containing nicotine vaccine can be developed for human use when a nonhuman B cell epitope is used for assistance in nicotine hapten processing and presentation. This hypothesis will be evaluated by the following specific aims: 1) To test YSFKPMPLaR-containing nicotine vaccines, which utilize nonhuman epitopes to assist hapten processing and presentation, for their ability to produce anti-nicotine Abs in rats immunized in the absence of added adjuvants, and 2) To evaluate the effectiveness of vaccination with the vaccine(s) from Aim 1 in attenuating nicotine-induced behavioral effects in two well-characterized rat models of nicotine dependence. A nicotine vaccine that satisfies these aims would be a candidate vaccine for human clinical trials in Treating nicotine dependence via vaccination as an approach for smoking cessation.